Fungal infections of the skin, hair and mucosae are mainly caused by dermatophytes, which induce pathologies known collectively as tinea, and by Candida albicans, which causes vulvovaginities and oral candidiases ("thrush"), among other syndromes. In recent years, oral candidiases have become more prevalent and intractable due to their appearance in immunocompromised patients, such as those infected with Human immunodeficiency Virus (HIV) or suffering from Acquired Immunodeficiency Syndrome (AIDS).
U.S. Pat. No. 3,717,655 discloses the preparation and use of imidazole derivatives for the topical treatment of fungal infections. 1-[2,4-dichloro-.beta.-(2,4-dichlorobenzyloxy)phenethyl]-imidazole nitrate, whose common name is miconazole nitrate, is disclosed as a broad-spectrum antifungal agent with a powerful activity against dermatophytes and Candida albicans.
Miconazole nitrate is currently used in several pharmaceutical forms (ointment, cream, powder, suppositories, etc.). The poor solubility of miconazole and other imidazole derivatives in aqueous solutions such as water and in polar solvents such as ethanol (0.03% and 0.76% weight/volume, respectively), however, forestalls their use in tinctures and sprays and thus limits their applicability to treating a broad range of fungal infections such as those caused by Trichophyton rubrum, Tricophyton mentagrophytes, Epidermophyton floccsum, and Candida albicans. In order to be pharmaceutically effective, they must be highly soluble (.gtoreq.2%) and remain in solution over a period of time no less than two years.
U.S. Pat. No. 4,912,124 discloses a solvent system for imidazole derivatives employing mixtures of a polar solvent, a polyhydric alcohol that acts as a solubilizing agent, a nonionic or amphoteric surfactant, and a cosmetic humectant. Using this solvent system, solutions containing at least 1% w/v imidazole derivatives can be formulated. A critical aspect of the patent's teaching is the use of a polyhydric alcohol or an ester- or alkyl-substituted derivative therof as a solubilizing agent.
What is needed in the art are improved pharmaceutical formulations comprising imidazole derivatives such as miconazole nitrate in the form of a tincture or spray with improved stability and solubility characteristics, in particular for treatment of fungal infections of the nail bed. Further it is desired that such imidazole derivatives remain in solution for a period of time greater than six months.